Patients who experience acute, transient or persistent pain often repor6t complete or partial loss of appetite. Despite its high prevalence, the neural basis of pain-induced anorexic behavior is unknown. The premise for this proposal is the association between pain and anorexia, which is particularly striking during attacks of migraine headache. The objectives of the current proposal are to gain novel understanding of the neurobiology of anorexia induced by pain using our animal model. The specific aims in this proposal have been born out of our ongoing basic and clinical studies on the pathophysiology of migraine and how intracranial pain signals research the hypothalamus. Specific Aim 1 will determine whether stimulus of the dura, which we use as a model for intracranial pain (such as migraine), can activate neurons in brain areas that mediate anorexia. Specific Aim 2 will identify the neural pathways that transmit intracranial pain signals to hypothalamic neurons that regulate feeding behavior. Specific Aim 3 will identify the chemical phenotype of the neurons activated by dural stimulation and determine whether they express molecules (such as CCK and leptin) that were shown recently to suppress appetite and used clinically to fight obesity. Specific Aim 4a will determine whether dural stimulation can suppress feeding behavior in our animal model and whether it resembles the suppression of feeding behavior during migraine attack in human subjects. Specific aim 4b will test our working hypothesis that the suppression of feeding behavior by intracranial pain is mediated by activation of parabrachial neurons that contain CCK and ventromedial hypothalamic neurons that exhibit receptors to anorexic neuropeptide CCK and/or the hormone leptin. This grant proposal offers a unique collaborative effort of expertise from the field of feeding behavior and the field of pain and migraine. This interdisciplinary approach provides an opportunity to use state-of-the-art techniques to examine neuroanatomical, neurophysiological, molecular, and behavioral aspects of the neural mechanism that enables pain to induce anorexia; a biological phenomenon of distinct clinical relevance that affects millions of pain patients in the US.